Characterization of two novel pathogenic variants at compound heterozygous status in lipase maturation factor 1 gene causing severe hypertriglyceridemia
Characterization of two novel pathogenic variants at compound heterozygous status in lipase maturation factor 1 gene causing severe hypertriglyceridemia
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DOI：
10.1016/j.jacl.2018.07.008
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发表时间：
2018-10-01
影响因子：
4.4
通讯作者：
Di Taranto, Maria Donata
中科院分区：
文献类型：
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作者：
Peterfy, Miklos;Bedoya, Candy;Di Taranto, Maria Donata
背景：严重高甘油三酯血症是一种罕见的疾病，其特征是甘油三酯水平高于1000 mg/dL （11.3 mmol/L）和急性胰腺炎。该疾病是由编码脂蛋白脂肪酶（LPL）、载脂蛋白A5、载脂蛋白C2、糖基磷脂酰肌醇锚定的高密度脂蛋白结合蛋白1和脂肪酶成熟因子1 （LMF1）基因的致病性变异引起的。目的：我们旨在确定严重高甘油三酯血症的遗传原因，并表征严重高甘油三酯血症患者的新变异。方法：先证者为重度高甘油三酯血症男性（甘油三酯1416 mg/dL， 16.0 mmol/L）；Proband的亲属也接受了筛查。遗传筛选包括对上述基因的直接测序和鉴定LPL基因的大重排。通过在转染的LMF1缺陷小鼠成纤维细胞中补充LPL成熟，实现了LMF1突变体的功能表征。结果：先证者及其患病兄弟是LMF1基因变异的复合杂合子，从未被鉴定为严重高甘油三酯血症c的病因[157delC；1351C>T]；410 c > T, p。[(Arg53Glyfs * 5)]; [(Ser137Leu)]。功能分析表明，p.（Arg53Glyfs*5）截断完全消除，p.（Ser137Leu）错义变异显著降低了LMF1的脂肪酶成熟活性。结论：除了一种新的截断变异外，我们首次描述了一种从功能上证明影响LMF1脂肪酶成熟功能的错义变异。这是第一例LMF1的复合杂合变异体在功能上被证明是严重高甘油三酯血症的病因。(C) 2018年全国血脂协会。版权所有。
BACKGROUND: Severe hypertriglyceridemia is a rare disease characterized by triglyceride levels higher than 1000 mg/dL (11.3 mmol/L) and acute pancreatitis. The disease is caused by pathogenic variants in genes encoding lipoprotein lipase (LPL), apolipoprotein A5, apolipoprotein C2, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, and lipase maturation factor 1 (LMF1).OBJECTIVE: We aim to identify the genetic cause of severe hypertriglyceridemia and characterize the new variants in a patient with severe hypertriglyceridemia.METHODS: The proband was a male showing severe hypertriglyceridemia (triglycerides 1416 mg/dL, 16.0 mmol/L); proband's relatives were also screened. Genetic screening included direct sequencing of the above genes and identification of large rearrangements in the LPL gene. Functional characterization of mutant LMF1 variants was performed by complementing LPL maturation in transfected LMF1-deficient mouse fibroblasts.RESULTS: The proband and his affected brother were compound heterozygotes for variants in the LMF1 gene never identified as causative of severe hypertriglyceridemia c.[157delC;1351C>T];[410C>T], p.[(Arg53Glyfs*5)];[(Ser137Leu)]. Functional analysis demonstrated that the p.(Arg53Glyfs*5) truncation completely abolished and the p.(Ser137Leu) missense variant dramatically diminished the lipase maturation activity of LMF1.CONCLUSIONS: In addition to a novel truncating variant, we describe for the first time a missense variant functionally demonstrated affecting the lipase maturation function of LMF1. This is the first case in which compound heterozygous variants in LMF1 were functionally demonstrated as causative of severe hypertriglyceridemia. (C) 2018 National Lipid Association. All rights reserved.